Abstract
The pathological manifestations of fatal cases of human hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) are characterized by inflammatory damage to the central nervous system (CNS). Here, the dynamic distribution of EV71 in the CNS and the subsequent pathological characteristics within different regions of neonatal rhesus macaque brain tissue were studied using a chimeric EV71 expressing green fluorescence protein. The results were compared with brain tissue obtained from the autopsies of deceased EV71-infected HFMD patients. These observations suggested that the virus was prevalent in areas around the blood vessels and nerve nuclei in the brain stem and showed a preference for astrocytes in the CNS. Interestingly, infected astrocytes within the in vivo and in vitro human and macaque systems exhibited increased expression of excitatory neurotransmitters and cytokines that also stimulated the neuronal secretion of the excitatory neurotransmitters noradrenalin and adrenalin, and this process most likely plays a role in the pathophysiological events that occur during EV71 infection.
Highlights
Hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) is an important viral infectious disease that has increasingly affected children in the Asia-Pacific region in recent years
Our observations in this study provide a conceptual framework for the pathophysiological process underlying EV71 infection in the central nervous system (CNS), which led us to hypothesize that infected astrocytes may play a major role in the pathogenesis of neurogenic pulmonary edema and cardiopulmonary failure
The experiments suggested that viral infection in these cells was dependent on phagocytosis and the presence of complement in at least the in vitro culture system, which suggests that the virus exhibits a preference for astrocytes compared with neurons, a finding that facilitated the elucidation of the pathogenesis of EV71 infection in the CNS
Summary
Foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) is an important viral infectious disease that has increasingly affected children in the Asia-Pacific region in recent years. We subsequently examined the pathological characteristics of different regions of neonatal rhesus macaque brain tissue and compared the findings to those of autopsies of deceased EV71-infected HFMD patients diagnosed with severe neurogenic pulmonary edema and cardiopulmonary failure Further investigations in both human and macaque in vivo and in vitro systems were performed to confirm our hypotheses that viral replication occurred in a few neurons but was mostly limited to astrocytes and that EV71 infection may increase the expression of pro-inflammatory cytokines, noradrenalin, and dopamine in astrocytes and stimulate the neuronal secretion of noradrenalin and adrenalin. Noradrenalin and adrenalin are both excitatory neurotransmitters that most likely play roles in the pathophysiological events that occur during EV71 infection
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